Nu-benzyl-nu-alkyl morpholinium compounds



Patented Sept. 3, 1946 N-BENZYL-N-ALKYL MoarnonrNIU COMPOUNDS Joseph B. Niederl, Victor Niederl; and Martin E. McGreal, Brooklyn, N. Y.

No Drawing. Continuation of application Serial.

No. 393,672, May 15, 1941.

This application January 1, 1943, Serial No. 471 024 1 Claim. (01. 260F241) ing N-benzyl-N-alkyl morp-holinium halides, the

N-alkylated morpholine is. treated with a benzyl halide. Generally. speaking, the reaction may be carried to completion at roomor at elevated temperaturesand in. the presencev or in the absence of an'inertsolvent. Thus, any. of the lower. molecular. N-alky-lated morpholines, such as N- methyl, N-ethy1, N-prop-yl, N-butyl, or. N-amyl morpholine; or any of the higher molecular alkylated morpholines, such as, N- lauryl, N-myristyl, N-cetyl or N-octadecyl morpholine, described in 'patentapplication Serial 'No. 435,638,, filed March 21, 1942, may be subjected to the action of benzyl chloride or benzyl bromide to yield the respective N-benZyl-N-alkyl morpholinium halides. a e

In another method for preparing the N-benzyl- N -alkylmorpholinium halides, N -benz yl morpholine having a boiling-point of 160.- to 1615 .C. is

reacted with a lowermolecular orhigher molec ular alkyl halide, such as, ethyl, methyl, -pro- Brian -WW1. and e amy odides or l llT' i iristyl, cetyl and octadecyl bromides andthe it:

Amon the Nrben yl-N-al IE QF EQ halides prepared in accordance with the previousl dis usse proce ses are:

N-benzyl-N-methyl morpholinium halides -N-benzyl-N-ethyl morpholinium halides N-benzyl- N-n-propyl morpholinium halides N-benzyl-N-n-butyl morpholinium halides N-benzyl-N-n-amyl morpholinium halides N-ber'izyl-N-laur'yl morpholinium halides li-benzyl-N-inyristyl mprpholinium halides N-benzyl-N-cetyl morpholinium halides? N-benzyl-N-octadecyl morpholinium halides N' ZXlTN.-PI1UYI marnholmium hali es W-hi1e itis not necessary to use solvents in carrying out the reactions of this'inventi hsq ei or diluents may be used, including esters, such as, ethyl acetatef hydrocarbons, such as, benzene, toluene, petroleum ether, and thdlkeyalcohols, such as, ethyl and methyl alcoholj ethers, such 2 as diethyi and diisopropyl ethers; and lilre inert solvents, In a special embodiment of the inventioh, the reaction carried out in the presence of asolvent which dissolves the reactants but pre (imitates out the reaction products, especially if the solvent is @001. Wheh operating in this manner, the "N-f-benZyl-N-alkyl morpholiniurn salts ma be separated" out in a purified form without the'necessity of removing the solvent. Various solvents may serve this dual purpose as a homogenizing and a crystallizing medium. For practical reasons ethyl acetate seems to be the most appropriate solvent of this type. It should be understood, therefore; that claims directed to reactions taking place in the presence of ethyl acetate encompass such equivalents. l In accordance with one embodiment of the invention; temperatures are regulated in such a manner that the reactants are retained in a liquid phase during th're'action. Generally speaking, water or. steam baths provide sufiiciently high temperatures'for such a purpose.

When the reactants are mixed together with out diluents of solvents; suitable concentrated aqueous solutions of the reaction productmay be formed merely by the addition of water without the necessity of expensive separatory, crystallizing or purifying'steps.

The following examples disclose illustrative embodiments of the invention but are not to be considered a limitation upon it.

Emmr e icNrbr z zeN-qlhfl rrh i chlorides One mole, 311 grams, of N-cetyl morpholine having E. f f 23 c. a a P. of 184 C. at 4 pressureri P1 435 a one liter round-bottonied iiasl; and"l 2 gram of freshly distilled benjzlyl chloride are added. The flash is sealed tig y y H dto forin a concentrated aqueous solution of en zlyl-N-cetyl morpholiniuni chloride, water 18 added directly to the reaction produep. Fofinstancf, the N benzy1-N-cety1 morpholiniumhhloride derived from the previously described reaction may be transferred to an appropriate vessel and mixed with 1748 ml. of water to form a 20% aqueous solution. In a like manner, aqueous solutions having a concentration of 5% to of N-benzyl-N-cetyl morpholim'um 3 chloride, may be prepared by dissolving the reaction product in the appropriate volume of water.

Such concentrated aqueous solutions of N-benzyl-N-cetyl morpholinium chloride are very valuable and convenient for preparing desired disinfecting and sterilizing solutions merely by further addition of water.

Similarly, one-tenth mole of freshl distilled N- cetyl morpholine and one-tenth mole of freshly distilled benzyl chloride may be reacted in an appropriate tube having a capacity of 50 to 60 cc. After the introduction of the reactants into the tube they are thoroughly mixed and the tube is sealed and placed in a boiling water bath. After 4 hours, the contents of the tube will solidify upon cooling. After 12 hours, the reaction is completed and the reaction product is soluble in water in all proportions. In order to crystallize out the N- benzyl-N-cetyl morpholinium chloride, the contents of the tube are transferred to a flask, such as, a 250 cc. Erlenmeyer flask, and boiled with 100 cc. of ethyl acetate. The boiling is continued until the entire contents of the tube are dissolved. Then, the resulting solution is allowed to stand at room temperature for one hour, whereupon 31 grams of N-benzyl-N-cetyl morpholinium chloride crystallize out. The crystals are filtered off and the mother liquor is concentrated to yield additional crystals of the quaternary ammonium salt.

The N-benzyl-N-cetyl morpholinium chloride produced as described hereinbefore begins to sinter at 85 C. and is completely melted at 150 C.

In a similar manner, by using appropriate N- alkyl morpholines, the following N-benzyl-N-alkyl morpholinium chlorides are produced:

The previously described processes for producing N-benzyl-N-alkyl morpholinium chlorides are generally applicable. Normally, one mole of freshly distilled N-alkyl morpholine is placed in a suitable reaction vessel which can be sealed or morpholinium chloride,

otherwise closed, such as in an autoclave, or in-' troduced into a reaction vessel provided with a reflux condenser having a drying tube attached to ensure thoroughly anhydrous conditions. Thereafter, one mole of freshly distilled benzyl chloride is added. The two reactants are mixed thoroughly and the reaction vessel closed. Then the reaction mixture preferably is heated to about 106 C. and the heating continued until the reaction mixture becomes solid on cooling and until it becomes completely soluble in water. This reaction usually requires from 4 to 12 hours.

After the reaction is completed, further working up of the reaction product depends upon whether the product is to be used as a crystalline solid or in concentrated aqueous solutions. When the crystallized product is desired. it is either crystallized out of the reaction mixture or is precipitated out by the addition of a suitable diluent, such as, ethyl acetate, diethyl ether, petroleum ether, benzene, toluene, or the like. Preferably, the N-benzyl-N-alkyl morpholinium chloride is then recrystallized from hot ethyl acetate.

When aqueous solutions are desired, the reaction mixture is merely distilled with an appropriate amount of water to yield, for example, concentrations of 50%, 30% or 20%. The reaction mass may be pre-treated with suitable adsorbents or subjected to filtration, to increase its purity, before being diluted with the water.

Example 2.-N-benzyl-N-allcyl morpholinium bromides One mole of freshly distilled N-alkyl morpholine is diluted with about 2 parts per volume of ethyl acetate and introduced into a suitable glass vessel. Thereafter, one mole of freshly distilled benzyl bromide is introduced into the reaction vessel. The reaction mass is thoroughly shaken and allowed to stand at room temperature. After about 12 hours, a nearly quantitative yield of the reaction product, N-benzyl-N-alkyl morpholinium bromide, is obtained. Thereupon, the crystals are filtered off and recrystallized from ethyl acetate. The mother liquor, upon concentration under reduced pressure, yields additional crystals of N- benzyl-N-alkyl morpholinium bromides.

For example, one-tenth mole, 31 grams, of N- cetyl morpholine is diluted with 50 ml. of ethyl acetate and introduced into a 250 ml. Erlenmeyer flask. Thereupon, one-tenth mole, 17 grams, of freshly distilled benzyl bromide is slowly intro duced into the flask. After the completion of the addition of the benzyl bromide, the mixture is thoroughly shaken, closed with a stopper and set aside at room temperature for at least 12 hours. At the end of this period of time, 40 gramsof N- benzyl-N-cetyl bromide have crystallized out. The crystals then may be filtered off and recrystallized from hot ethyl acetate. If the mother liquor is concentrated under reduced pressure, additional crystals of the N-benzyl-N-cetyl morpholinium bromide will form. This operation may be repeated until all the quaternary morpholinium salt is isolated.

The N-benzyl-N-cetyl morpholinium bromide begins to sinter at about C. and is completely melted at about C.

In a similar manner, the following N-benzyl-N- alkyl morpholinium bromides have been prepared by reacting appropriate N-alkyl morpholines with benzyl bromide.

N-benzyl-N-methyl morpholinium bromide, M. P.

N-benzyl-N-ethyl morpholinium bromide, M. P.

N-benzyl-N-lauryl morpholinium bromide, M. P.

N-benzyl-N-myristyl morpholinium bromide, M.

N-benzyl-N-cetyl morpholinium bromide, M. P.

N-benzyl-N-octadecyl morpholinium bromide,

M. P. C. v

N-benzyl-N-phenyl morpholinium bromide, M. P,

The previous examples disclose reactions involving molar ratios. An excess of either of the reagents may be present, however, without deleteriously affecting the results since the reactions will take place in equimolar proportions.

The N-benzyl-N-alkyl morpholinium halides prepared as previously described may be used for the preparation of other N-benzyl-N-alkyl mor- 5 pholinium salts. For instance, N-benzyl-N-alkyl morpholinium sulfates, including the alkyl sulfates, such as, methoand ethosulfates, or nitrates and th like, are obtained by treating the halides with silver, sodium or potassium salts of the appropriate mineral or organic acids or mono esters. Thus, the sulfates and nitrates are prepared by treating the chlorides or bromides, respectively, with silver sulfate or silver nitrate. The alkyl sulfates are best prepared by refluxing a halide with sodium or potassium salt of the respective mono alkyl sulfates, such as, sodium methosulfate or potassium ethosulfate, and the like, dissolved in an alcoholic solution. Compounds produced in this manner include N-benzyl-N-alkyl morpholinium salts having from 12 to 18 carbon atoms in the alkyl radical, such as, N-benzyl-N- morpholinium sulfate, N-benzyl-N-cetyl morpholinium ethosulfate, N-benzyl-N-cetyl morpholinium methosulf ate, and the like.

It will be understood that the embodiments of my invention described in the specification and illustrated by the examples are only illustrative of the compounds and the processes by which they are produced. Various modifications can be made without departing from the principles of the invention.

We claim:

N-benzyl-N-cetyl morpholinium ethosulfate.

JOSEPH B. NIEDERL. vVICTOR NIEDERL.

MARTIN E. MCGREAL. 

